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Physiological effects of cortisol
In normal release, cortisol (like other glucocorticoid agents) has widespread actions which help restore homeostasis after stress. (These normal endogenous functions are the basis for the physiological consequences of chronic stress - prolonged cortisol secretion.). It has been proposed that its primary function is to inversely mobilize the immune system to fight potassium losing diarrhea diseases Weber CE (1998) “Cortisol’s purpose.” Medical Hypotheses 51; 289-292.. Its odd attributes all support this. Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and such physiological stressors as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion or extremes of temperature. Cortisol levels may also be different for people with autism or Asperger's syndrome. There is also significant individual variation, although a given person tends to have consistent rhythms. THe effects of raised levels are widespread and include: ;Insulin: It acts as a physiological antagonist to insulin by decreasing glycogenesis (formation of glycogen) and promotes breakdown of lipids (lipolysis), and proteins, and mobilization of extrahepatic amino acids and ketone bodies. This leads to increased circulating glucose concentrations (in the blood) by increasing gluconeogenesis. There is an increased glycogen breakdown in the liver . Freeman, Scott (2002). Biological Science. Prentice Hall; 2nd Pkg edition (December 30, 2004). ISBN 0-13-218746-9. Prolonged cortisol secretion causes hyperglycemia. Cortisol has no effect on insulin Barseghian, G.; Rachmiel, L.; Epps, P. (1982) “Direct Effect of Cortisol and Cortisone on Insulin and Glucagon Secretion”. Endocrinology 111: 1648,.. The reason why in vivo experiments seem to deny this is that cortisone greatly inhibits insulin . So the cortisone-cortisol equilibrium may explain why in vivo experiments contradict the cortisol effect Curry, D.L.; Bennett, L.L. (1973) “Dynamics of Insulin Release by Perfused Rate Pancreas: Effects of Hypophysectomy, Growth Hormone, Adrenocorticotropic Hormone and Hydrocortisone”. Endocrinology 93: 602,.. Cortisol does cause serum glucose to rise, but this is probably an indirect effect caused by stimulation of amino acid degradation, especially that derived from collagen in the skin. Loss of collagen from skin by cortisol is ten times greater than from all other tissue in the rat. Houck, J.C.; Sharma, V.K.; Patel, Y.M.; Gladner, J.A. (1968) “Induction of Collagenolytic and Proteolytic Activities by AntiInflammatory Drugs in the Skin and Fibroblasts”. Biochemical Pharmacology 17: 2081,. ;Amino acids:Cortisol raises the free amino acids in the serum. It does this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis. Manchester, K.L., “Sites of Hormonal Regulation of Protein Metabolism. p. 229”, Mammalian Protein H.N., Ed.. Academic Press, New York. On p273. Cortisol (as opticortinol) probably inversely inhibits IgA precursor cells in the intestines of calves Husband, A.J.; Brandon, M.R.; Dascelles, A.K. (1973) “The Effect of Corticosteroid on Absorption and Endogenous Production of Immunoglobulins in Calves”. Aust. Journal of Exp. Biol. Med. Sci. 55: 707,.. Cortisol also inhibits IgA in serum, as it does IgM, but not IgE. Posey, W.C.; Nelson, H.S.; Branch, B. and Pearlman, D.S. (1978) “The Effects of Acute Corticosteroid Therapy for Asthma on Serum Immunoglobulin Levels”. J. Allergy Clin. Immunol. 62: 340,. ;Gastric secretion:Cortisol stimulates gastric acid secretion Soffer, L.J.; Dorfman, R.I.; Gabrilove, J.L,. “The Human Adrenal Gland”. Febiger, Phil.. Gastric acid secretion would increase loss of potassium into the stomach during diarrhea as well as acid loss. Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate excretion of ammonium ion by inactivation of renal glutaminase enzyme Kokshchuk, G.I.; Pakhmurnyi, B.A. (1979) “Role of Glucocorticoids in Regulation of the Acid-Excreting Function of the Kidneys”. Fiziol. Z H SSR I.M.I.M. Sechenova 65: 751,.. Net chloride secretion in the intestines is inversely decreased by cortisol in vitro (methylprednisolone) Tai, Y.; Decker, R.A.; Marnane, W.G.; Charney, A.N.; Donowitz, M. (1981) "Effects of Methylprednisolone on Electrolyte Transport by Rat Ileum in Vitro." American Journal of Physiology 240-G346: 70,.. ;Sodium:Cortisol inhibits loss of sodium from small intestines of mammals. Sandle, G.I.; Keir, M.G.; Record, CO. (1981) “The Effect of Hydrocortisone on the Transport of Water, Sodium, and Glucose in the Jejunum”. Scandinavian Journal of Gastroenterol. 16: 667,.. However sodium depletion does not affect cortisol Mason, P.A.; Fraser, R.; Morton, J.J. (1977) “The Effect of Sodium Deprivation and of Angiotensin II Infusion on the Peripheral Plasma Concentration of 18 Hydroxycorticosterone, Aldosterone, and Other Corticosteoids in Man”. Steroid Biochemistry 8: 799,, so cortisol is not used to regulate serum sodium. Cortisol’s purpose may originally had been centered around moving sodium because cortisol is used to stimulate sodium inward for fresh water fish and outward for salt-water fish Gorbman, A.; Dickhoff, W.W.; Vigna, S.R.; Clark, N.B.; Muller, A.F,. “Comparative Endocrinology”. John Wiley and Sons, New York.. ;Potassium:Sodium loads augments the intense potassium excretion by cortisol, and corticosterone is comparable to cortisol in this case Muller AF Oconnor CM, ed. (1958) “An International Symposium on Aldosterone”, page 58. Little Brown & Co.. In order for potassium to move out of the cell, cortisol moves in an equal number of sodium ions Knight, R.P., Jr.; Kornfield, D.S.; Glaser, G.H. & Bondy, P.K. (1955) “Effects of Intravenous Hydrocortisone on Electrolytes in Serum and Urine in Man”. Journal of Clinical Endocrinology 15: 176-181,.. It can be seen that this should make pH regulation much easier, unlike the normal potassium deficiency situation in which about 2 sodium ions move in for each 3 potassium ions that move out, which is closer to the deoxycorticosterone effect. Nevertheless, cortisol consistently causes alkalosis of the serum, while in a deficiency pH does not change. Perhaps this may be for the purpose of bringing serum pH to a value most optimum for some of the immune enzymes during infection in those times when cortisol declines. Potassium is also blocked from loss in the kidneys directly somewhat by decline of cortisol (9 alpha fluorohydrocortisone) Barger, A.C.; Berlin, R.D.; Tulenko, J.F. (1958) “Infusion of Aldosterone, 9 Alpha Fluorohydrocortisone, and Antidiuretic Hormone into the Renal Artery of Normal and Adrenalectomized Unanesthetized Dogs: Effect on Electrolyte and Water Excretion”. Endocrine. 62: 804,.. ;Water:Cortisol also acts as a water diuretic hormone. Half the intestinal diuresis is so controlled Sandle, G.I.; Keir, M.G.; Record, CO. (1981) “The Effect of Hydrocortisone on the Transport of Water, Sodium, and Glucose in the Jejunum”. Scandinavian Journal of Gastroenterol. 16: 667,.. Kidney diuresis is also controlled by cortisol in dogs. The decline in water excretion upon decline of cortisol (dexamethasone) in dogs is probably due to inverse stimulation of antidiuretic hormone (ADH or arginine vasopressin), the inverse stimulation of which is not overridden by water loading. Boykin, J.; de Torrent, A.; Erickson, A.; Robertson, G.; Schrier, R.W. (1978) “Role of Plasma Vasopressin in Impaired Water Excretion of Glucocorticoid Deficiency”. Journal of Clinical Investigation 62: 738,.. Humans also use this mechanism Dingman, J.F.; Gonzalez-Auvert Ahmed, A.B.J.; Akinura, A. (1965) “Antidiuretic Hormone in Adrenal Insufficiency”. Journal of Clinical Investigation 44: 1041,. and other different animal mechanisms operate in the same direction. ;Copper:It is probable that increasing copper availability for immune purposes is the reason why many copper enzymes are stimulated to an extent which is often 50% of their total potential by cortisol Weber, C.E (1984). “Copper Response to Rheumatoid Arthritis”. Medical Hypotheses 15: 333-348, on p337,.. This includes lysyl oxidase, an enzyme which is used to cross link collagen and elastin Weber, C.E. (1984) “Copper Response to Rheumatoid Arthritis”. Medical Hypotheses 15: 333,.on p334.. Particularly valuable for immunity is the stimulation of superoxide dismutase by cortisol Flohe, L.; Beckman, R.; Giertz, H.; Loschen, G. “Oxygen Centered Free Radicals as Mediators of Inflammation. p. 405”, Oxidative Stress (Sies H, ed) Academic Press, New York. since this copper enzyme is almost certainly used by the body to permit superoxide to poison bacteria. Cortisol causes an inverse four or five fold decrease of metallothionein, a copper storage protein, in mice Piletz, J.E.; Herschman, H.R. (1983) “Hepatic Metallothionein Synthesis in Neonatal Mottled-Brindled Mice”. Biochem. Genet. 21: 465. (however rodents do not synthesize cortisol themselves),. This may be to furnish more copper for ceruloplasmin synthesis or release of free copper. Cortisol has an opposite effect on alpha aminoisobuteric acid than on the other amino acids Chambers, J.W.; Georg, R.H. and Bass, A.D. (1965) “Effect of Hydrocortisone and Insulin on Uptake of Alpha Aminoisobutyric Acid by Isolated Perfused Rat Liver”. Mol. Pharmacol. 1: 66,.. If alpha aminoisobuteric acid is used to transport copper through the cell wall, this anomaly would possibly be explained. ;Immune system:Cortisol can weaken the activity of the immune system . Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor. Cortisol has a negative feedback effect on interleukin-1 Besedovsky, H.O.; Del Rey, A.; Sorkin, E. (1984) "Integration of Activated Immune Cell Products in Immune Endocrine Feedback Circuits." p. 200 in Leukocytes and Host Defense Vol. 5 J.J.; Jacobs, D.M., eds. Alan R. Liss, New York,. which must be especially useful in combating diseases, such as the endotoxin bacteria, that gain an advantage by forcing the hypothalamus to secrete a hormone called CRH. The suppressor cells are not affected by GRMF, Fairchild, S.L.; Shannon, K.; Kwan, E.; Mishell, R.I. (1984) "T-Cells Derived Glucocorticosteroid Lymphocytes and a T-Cell Hybridoma." Journal of Immunology 132: 821, so that the effective set point for the immune cells may be even higher than the set point for physiological processes. It reflects leukocyte redistribution to lymph nodes, bone marrow, and skin. Acute administration of corticosterone (the endogenous Type I and Type II receptor agonist), or RU28362 (a specific Type II receptor agonist), to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are not affected by cortisol Onsrud M Thorsby E (1981) “Influence of in vivo hydrocortisone on some blood lymphocyte subpopulations 1. effect on natural killer cell activity”. Scand. J. Immunol. 13; 573-579.. ;Bone metabolism: It lowers bone formation thus favoring development of osteoporosis in the long term. Cortisol moves potassium out of cells in exchange for an equal number of sodium ions as mentioned above. This can cause a major problem with the hyperkalemia of metabolic shock from surgery. ;Memory: It cooperates with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future. However, long-term exposure to cortisol results in damage to cells in the hippocampus. This damage results in impaired learning. The desirability of inhibiting activity during infection is no doubt the reason why cortisol is responsible for creating euphoria, Newsholme, E.A., Leech, A.R. “Biochemistry for the Medical Sciences. John Wiley & Sons, New York, on p736.. The desirability of not disturbing tissues weakened by infection or of not cutting off their blood supply could explain the inhibition of pain widely observed for cortisol. ;Additional effects: * It increases blood pressure by increasing the sensitivity of the vasculature to epinephrine and norepinephrine. In the absence of cortisol, widespread vasodilation occurs. * It inhibits the secretion of corticotropin-releasing hormone (CRH), resulting in feedback inhibition of ACTH secretion. Some researchers believe that this normal feedback system may break down when animals are exposed to chronic stress. * It increases the effectiveness of catecholamines. * It allows for the kidneys to produce hypotonic urine. * It has anti-inflammatory effects by reducing histamine secretion and stabilizing lysosomal membranes. The stabilization of lysosomal membranes prevents their rupture, thereby preventing damage to healthy tissues. * It stimulates hepatic detoxification by inducing tryptophan oxygenase (to reduce serotonin levels in the brain), glutamine synthase (reduce glutamate and ammonia levels in the brain), cytochrome P-450 hemoprotein (mobilizes arachidonic acid), and metallothionein (reduces heavy metals in the body). * In addition to the effects caused by cortisol binding to the glucocorticoid receptor, because of its molecular similarity to aldosterone, it also binds to the mineralocorticoid receptor. (It binds with less affinity to it than aldosterone does, but the concentration of blood cortisol is higher than that of blood aldosterone.) References category:Hydrocorti [[category:Physiological effects of cortisol